A new syndrome;termed, Immune reconstitution inflammatory syndrome (IRIS) has emerged in individuals with HIV/AIDS. This disease may occur soon after starting treatment with antiretroviral drugs and in some it may rapidly progress to cause a severe encephalitis resulting in death. As antiretroviral therapy is now becoming available worldwide, IRIS is emerging as a single most important complication with a major impact on the ability to treat large populations with HAART where viral loads cannot often be measured. Understanding the pathogenesis of this syndrome and developing new approaches for treatment are critically important in our battle against AIDS. In individuals with IRIS affecting the brain, there is massive infiltration of T cells. While it is clear that activated T cells can cause neuronal injury, it remains unknown how these cells get activated and it is also unknown as to what type of T cells enter the brain. In this grant proposal the applicant will characterize the T cell infiltrates in autopsy brain tissue from individuals who have been treated with antiretroviral drugs and also take advantage of archival tissue from SIV infected animals to determine the types of cell infiltrating the brain at different stages of infection. The subcellular mechanisms by T cell get activated by HIV infected reservoirs will also be determined. The Tat protein, the production of which is not impacted by antiretroviral drugs will be used to activate the T cells in vitro and to characterize the signaling cascades involved in T cell activation. We will also determine the epitopes of Tat that mediate T cell activation. We will determine the potential of Tat proteins from different clades of HIV to activate T cells. In this fellowship application, the pre- doctoral fellow will be closely mentored to develop skills in HIV research and neuroimmunology. A detailed plan for training and mentorship is presented. PUBLIC HEALTH RELEVANCE: This research is important to public health as antiretroviral therapy is now becoming available worldwide;IRIS is emerging as a single most important complication with a major impact on the ability to treat large populations with antiretroviral drugs. Understanding the pathogenesis of this syndrome and developing new approaches for treatment are critically important in our battle against AIDS.